Fludarabine Phosphate

Contraindications

• Known hypersensitivity to fludarabine and/or any ingredient in the formulation.1 95

Warnings/Precautions

Warnings

Severe, potentially irreversible or fatal neurologic effects (e.g., delayed, progressive encephalopathy and blindness, coma) reported;1 2 3 5 6 9 29 30 31 45 95 manifestations usually appear 21–60 days after completion of a course of therapy.1 2 29 30 31 95

Neurotoxicity appears to be dose related:1 2 3 6 9 29 30 31 45 95 usually occurring with dosages higher than those currently recommended for CLL.1 2 3 5 6 9 29 30 31 41 45 However, such toxicity may occur rarely at relatively low dosages.1 3 5 9 30 45 52 95

Monitoring for visual changes as evidence of neurotoxicity has been suggested.30

Risk of severe, cumulative, often reversible, myelosuppression (e.g., anemia, thrombocytopenia, neutropenia).1 2 3 4 5 6 9 22 23 39 95 95

Dosage adjustment and interruption of therapy and/or transfusions may be needed depending on severity of myelosuppression.9 Recovery of neutrophil and platelet count usually is complete within 5–7 weeks after discontinuance of therapy, but occasionally may require longer periods.87

Risk of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes fatal.1 95 Clinically significant cytopenia may last 2–12 months.1 95

Risk of life-threatening and sometimes fatal autoimmune hemolytic anemia, may recur upon rechallenge; close monitoring for hemolysis recommended.1 95 Not known whether corticosteroids are beneficial for management of these hemolytic episodes.1 95

Possible transfusion-associated graft-versus-host disease following transfusion of nonirradiated blood products.1 95 Consider use of irradiated blood products in patients requiring blood transfusions.1 95

Risk of severe and/or fatal pulmonary toxicity (e.g., pneumonitis) when administered concomitantly with pentostatin; do not use fludarabine with pentostatin.1 8 87 95 (See Specific Drugs under Interactions.)

May cause fetal harm (skeletal malformations, external deformities); avoid pregnancy during therapy.1 95

Use during pregnancy only in life-threatening situations or severe disease when safer drugs cannot be used or are ineffective.80 87

If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1 95

Sensitivity Reactions

Possible pulmonary hypersensitivity (diffuse interstitial pneumonitis characterized by dyspnea, hypoxia, cough, and pulmonary infiltrates).1 3 5 6 9 35 60 51 95

Interstitial pneumonitis usually delayed, occurring 3–28 days after administration of the third or later course of therapy.2 5 6 35 50

General Precautions

Highly toxic, very low therapeutic index; therapeutic response is unlikely without some evidence of toxicity.1 3 4 5 6 9 29 30 31 41 45 (See Boxed Warning.) Severe toxicity most likely in poor risk patients (e.g., geriatric patients, those with impaired renal or bone marrow function), but fatality may occur in those in relatively good condition.

Administer only under supervision of a qualified clinician experienced in the use of cytotoxic therapy.1 9 95

Closely observe for signs of hematologic and nonhematologic toxicity during therapy.1 30 65 95

If severe adverse effects occur, discontinue therapy or reduce dosage and institute appropriate measures as necessary.1 9 65 87 95

May occur as a result of CLL treatment.1 3 6 9 53 65 95

Increased risk in patients with large initial tumor burden.1 95

Closely monitor such patients and take appropriate precautions.1 95 Consider potential benefit of prophylactic allopurinol, adequate hydration, and/or urinary alkalinization.53 65 80 87

Specific Populations

Category D.

Not known whether fludarabine is distributed into milk.1 95 Discontinue nursing or the drug.1 95

Safety and efficacy not established.1 80 87 95

In clinical studies in a limited number of pediatric patients with certain cancers (e.g., acute leukemia, solid tumors),2 5 43 adverse effect profile generally was similar to that in adults.5 43 87

Bone marrow suppression (particularly thrombocytopenia), fever, chills, asthenia, rash, nausea, vomiting, diarrhea, and infection were reported.1 95 Pulmonary hypersensitivity and peripheral neuropathy not reported.1 95

Safety and efficacy in geriatric patients have not been studied specifically to date; however, CLL, for which safety and efficacy have been established,1 2 3 4 6 9 14 15 20 21 58 occurs principally in patients >50 years of age.24 58 61

Possible increased risk of fludarabine-induced toxicity due to age-related decrease in renal function.1 26 95 Closely monitor such patients (especially those with advanced Rai stage CLL)4 and adjust dosage accordingly.1 95

Clearance of fludarabine directly correlates with creatinine clearance.1 41 80 87 95

Possible increased risk of fludarabine-induced toxicity;1 2 3 95 monitor closely for excessive toxicity.1 95

Adjust dosage carefully in patients with impaired renal function;1 41 80 87 95 reduce dosage in those with moderate renal impairment.1 95 Do not use fludarabine in patients with severe renal impairment.1 95 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea and/or vomiting,1 2 3 4 6 9 22 23 95 anorexia,1 9 95 diarrhea,1 3 4 6 22 95 GI bleeding,1 9 95 fever,1 3 4 22 95 chills,1 95 rash,1 2 3 4 6 9 22 95 urinary tract infection,1 9 95 edema,1 3 9 95 cough,1 4 95 dyspnea,1 4 95 upper respiratory infection,1 9 95 infection,1 3 4 22 38 95 weakness,1 3 9 95 pain,1 9 95 malaise,1 9 22 95 fatigue,1 9 22 95 paresthesia,1 3 9 95 visual disturbances.19 23 39

Pharmacokinetic parameters generally are expressed in terms of fludarabine (2-fluoro-ara-A) and fludarabine triphosphate (2-fluoro-ara-ATP).80 81

Distribution

Extent

Widely distributed,2 9 69 80 with highest concentrations in the liver, kidneys, and spleen.2 9 70 85

Extent of distribution into CNS in humans is not known.2 3 5 6 9 29 30 31 45

Apparently crosses the placenta.1 95 Not known whether fludarabine is distributed into human milk.1 95

Plasma Protein Binding

Approximately 19–29%.1 95

Special Populations

AUC is similar in patients with moderate renal impairment (Clcr 17–41 mL/minute per 1.73 m2) to those with normal renal function.1 95

Elimination

Metabolism

Fludarabine monophosphate is rapidly and completely dephosphorylated to fludarabine (2-fluoro-ara-A; an active metabolite) and then phosphorylated intracellularly via deoxycytidine kinase to fludarabine triphosphate (2-fluoro-ara-ATP; an active metabolite).1 2 3 4 5 6 7 62 66 67 68 69 70 75 76 77 78 79 95

Elimination Route

Excreted principally in urine as fludarabine (2-fluoro-ara-A).1 41 95

Half-life

Terminal half-life is about 20 hours.1 95

Special Populations

Total body clearance is 124 and 172 mL/minute in patients with moderate renal impairment (Clcr 17–41 mL/minute per 1.73 m2) and in those with normal renal function, respectively.1 95

• Exact mechanism(s) not fully elucidated, but appears to involve inhibition of α-DNA polymerase, ribonucleotide reductase, and DNA primase through competition with the physiologic substrate, deoxyadenosine triphosphate, resulting in inhibition of DNA synthesis.1 2 3 4 5 6 7 95

• T cells are more sensitive than B cells to fludarabine’s cytotoxic effects;2 4 drug is highly active against B-cell lymphoproliferative disorders, including CLL.1 2 3 4 6 9 14 15 20 21 58 64 Cytolytic effect appears to be relatively rapid even in neoplasms that are characterized by a slow proliferative rate.9 53

• Importance of immediately informing clinician if fever, sore throat, or unusual bleeding or bruising occurs.80 87

• Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy, advise pregnant women of risk to the fetus.1 95 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1 95

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

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